Abstract
Amicoumacin A is an antibiotic that was recently shown to target bacterial ribosomes. It affects translocation and provides an additional contact interface between the ribosomal RNA and mRNA. The binding site of amicoumacin A is formed by universally conserved nucleotides of rRNA. In this work, we showed that amicoumacin A inhibits translation in yeast and mammalian systems by affecting translation elongation. We determined the structure of the amicoumacin A complex with yeast ribosomes at a resolution of 3.1 Å. Toxicity measurement demonstrated that human cancer cell lines are more susceptible to the inhibition by this compound as compared to non-cancerous ones. This might be used as a starting point to develop amicoumacin A derivatives with clinical value.
Highlights
Development of small molecule translation inhibitors is needed for progress in antibacterial as well as anticancer therapy[1,2]
Structural study of the amicoumacin A in the complex with bacterial 70S ribosome showed that inhibitor mediates additional contacts between mRNA and rRNA in the small ribosomal subunit E-site
We created a set of luciferase mRNA reporter constructs that included both cap-dependent and IRES-dependent transcripts
Summary
Development of small molecule translation inhibitors is needed for progress in antibacterial as well as anticancer therapy[1,2]. In a recent study[7], X-ray crystallographic structure of amicoumacin A bound to a Thermus thermophilus ribosome as well as biochemical and genetic analysis of bacterial translation inhibition has been reported. It appeared that amicoumacin A binds a conserved site between the E-site mRNA codon and 16S rRNA. The crystal structure of bacterial ribosome in complex with amicoumacin revealed that antibiotic interacts with universally conserved nucleotides of the small subunit rRNA7. This suggests that amicoumacin A may target the eukaryotic ribosome. While the overall binding site of amicoumacin A in eukaryotic ribosomes appeared to be the same as in bacterial ones, certain differences in the elements of the binding site may provide a framework for designing selective inhibitors on the basis of the amicoumacin A scaffold
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